(Absorption and Bioavailability Enhancement

of Pharmaceutical Oral Dosage Forms)

..

1.

2.

3.

2


:

(biological membrane)
(absorption) (secretion)

 (blood-brain barrier)
proximal kidney tubule
11
(bimolecular lipid) phospholipids, cholesterol fatty acid
esters (hydrophobic)
(hydrophilic)

(un-ionized form)

1 phospholipid 2



1

2 1

 (buccal)
(sublingual) (stomach) (intestine) (rectum)
(gastrointestinal tract)
pH (hydrochloric acid)
(digestive enzymes) pH
(ionization)
21
21 pH 6.8

nitroglycerin
pH 1 3 hydrochloric acid

erythromycin
erythromycin
erythromycin
esterified derivative
erythromycin ethylsuccinate erythromycin
estolate
(small intestine) pyloric
sphincter (stomach emptying
time)

pH pH pH
(enteric coating)

villi microvilli
3

 2
6 10
villi microvilli pH

microflora
1
3
vascular network superior vena cava
rectum inferior middle hemorrhoidal vein inferior
vena cava splanchnic circulation
portal vein
first-pass effect
MOUTH
STOMACH
SMALL & LARGE
INTESTINE
RECTUM

3. 1

4
2
4

 2
(dosage form)
4


(bioavailability)

(aqueous solutions) > (aqueous suspensions) >
(solid dosage forms)

(Aqueous solutions)


(cosolvent)
(solubilizing agent)

free acid


1.
2. (complexation)


3. micelles
4.
(viscosity inducing agent)

 (Aqueous suspensions)







1.
2.
3.
(suspending agent)
4. (surfactant) (wetting agent)
(flocculating agent)
(deflocculating agent)
5.
(Liquid-filled capsules)

hydroxypropyl methylcellulose (HPMC)
(nonaqueous solution)
(water-miscible vehicle) (thermal
properties)


/

()



(emulsion) (nanoemulsion)
(microemulsion)
6




digoxin polyethylene glycol, ethanol
propylene glycol (soft capsule)




(digestable oil)



(non-digestable oil) (partition)

(interfacial area)

1. (solubility)

2.
3. (hydrophilic)
(lipophilic)
4. (emulsifying agent)

5. ()
6.

 (Powder-filled capsules)
HPMC

(diluent) (lubricant)

5 sorbitol lactose

dicalcium
phosphate tetracycline calcium-tetracycline
complex

1.
2. (salt form)
3.
4.
5.
6. (adsorption)

7.
8.
9.

10.

 5
[a] [b]
2
(Uncoated-tablets)






1. (physicochemical properties)
(wettability)
(surface area) (crystal form)
2. (binder)
(disintegrant)
3.
9

4. (compaction pressure)
5.
6.
(Coated tablets)




(Enteric coated tablets)
(enteric coating)

(onset)

30
(Methods for enhancing of bioavailability)3
2
(pharmaceutically-dependent approach)

(pharmacokinetically dependent approach)

(permeability)
/


(drug metabolic fate)
(drug distribution) (excretion profile)
10

 (pharmaceutical approach)


(dissolution rate-limited absorption)







(micronization)


(metastable
polymorph form) pH










levodopa

Nishimura, et al4
(effervescent enteric coated tablet) levodopa

hydroxypropyl methylcellulose phthalate
levodopa
11



levodopa decarboxylase
dopamine 5

tetracycline dicalcium phosphate
amphetamine sodium carboxymethylcellulose phenobarbitone
polyethylene glycol 40002
phenytoin sodium
calcium sulfate dihydrate
(phenytoin overdose) lactose
calcium sulfate dihydrate phenytoin
calcium-phenytoin complex 6
lactose
(Buffered tablets)
Levy7,8 (buffered tablet
formulations) aspirin

penicillin
Stavchansky, et al9 relative bioavailability sarpicillin
methoxymethyl ester hetacillin anhydrous ampicillin
3 (buffer)

sarpicillin
(Particle size)

(micronized particle)

6 phenacetin 3

12


nitrofurantoin 7
microcrystalline form 100 m
macrocrystalline form (74-177 m)

6 phenacetin 6
1.5 g10

7 nitrofurantoin
100 mg [a] [b] 11
13

Solid Dispersion

solid dispersion solid dispersion
matrix (watersoluble carrier) (colloid)


solid dispersion 3
1. Melting Fusion method




matrix
(stainless steel)
2. Melting-solvent method
melting method Chiou Smith12
solid dispersions

spray congealing

3. Solvent method Coprecipitation method

Tachibana Nakamura13 chloroform
polyvinylpyrrolidone chloroform
coprecipitate

solid dispersion
114

14

 1. solid dispersion14

Afeditab
Certican
Cesamet

Nifedipine
Everolimus
Nabilone

Fenoglide
Gris-PEG
Incivek (US)

Fenofibrate
Griseofulvin
Telaprevir

Incivo(Europe)

Telaprevir

Elan/Watson
Novartis
Valeant
Pharmaceuticals
LifeCycle Pharma
Novartis/Pedinol
Vertex
Pharmaceuticals
Janssen
Pharmaceuticals

BCS class

2
Poloxamer PVP
3
HPMC
2 4
PVP

Melt/absorb
Melt spray drying
Melt extrusion

2
2
2 4

PEG
PEG
HPMCAS

Spray melt
Melt extrusion
Spray drying

2 4

HPMCAS

Spray drying

-, - -cyclodextrin cyclic oligosaccharide glucose 6,
7 8
inclusion complex
cyclodextrin

(membrane permeability) dissociation constant
cyclodextrin
cyclodextrin
-cyclodextrin cyclodextrin
( 6.5oA) 3
Uekama15-17 inclusion complex
cyclodextrin -cyclodextrin -cyclodextrin ( 8)
(Surface active agents)

18

/

15

 8. phenytoin phenytoin phenytoin-cyclodextrin-epichlorhydrin complex ( 300 mg ) 17

9. surfactant spironolactone
spironolactone polysorbate 8019
9 steroid 4
spironolactone polysorbate 80 19
3
(pharmacokinetic properties)

16



(partition coefficient)

new drug application (NDA)

pH


(half-life)

surface
activity

(
)
(dissolution-limited drug absorption)

17

 (Aqueous solubility)



sodium potassium
calcium aluminum

penicillin sodium potassium penicillin
G calcium
sodium potassium amine penicillin G procaine
penicillin penicillin
penicillin
potassium sodium
procaine penicillin
barbiturate sodium
phenytoin
sodium
(acid
salt)

hydrochloride sulfate
epinephrine hydrochloride, borate bitartrate
bitartrate
hydrochloride tetracycline amphoteric
hydrochloride
calcium


penicillin G methicillin

18

ampicillin 180 electron withdrawing group

-carbon atom hydrolytic cleavage -lactam ring
-methyl group ephedrine
epinephrine methyl group

1.
Swarbrick J, Boylan JC. Encyclopedia of pharmaceutical technical technology, Volume
1. New York: Marcel Dekker, 1988: 1-14.
2.
Ashford M. BioavailabilityPhysicochemical and dosage form factors. In: Aulton MC
and Taylor KMG eds. Aultons pharmaceutics: the design and manufacturing of
medicines. London: Churchill Livingstone, 2013: 324-333.
3.
Abdou HM. Dissolution, bioavailability & bioequivalence. Easton: Mack Publishing
Company, 1989: 277, 455-466.
4.
Nishimura K, Sasahara K, Arai M, Nitanai T, Ikegami Y, Morioka T, Nakajima E.
Dosage form design for improvement of bioavailability of levodopa. VI. Formulation of
effervescent enteric coated tablets. J Pharm Sci 1984; (73): 942-946.
5.
Cotzicas G, Papavasilious P, Gellene R. Modification of parkinsonism-chronic treatment
with L-dopa. New Eng J Med 1969; (280): 337-345.

19

6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.

17.

18.

19.

Tyler JH, Eadie MJ, Sutherland JM, Hooper WD. Outbreak of anticonvulsant
intoxication in an Australian city. Br Med J 1970; 4(5730): 271-273.
Levy G. The influence of solubility on the rate of gastrointestinal absorption of aspirin.
Clin Pharmacl Ther 1963; (4): 476-479.
Levy G. Effect of dosage form on drug absorption: a frequent variable in clinical
pharmacology. Arch Interpharmacodyn 1964; 152(1-2): 59-68.
Stavchansky S, et al. Evaluation of the bioavailability of sarpicillin, the methoxymethyl
ester of hetacillin, in humans. J Pharm Sci 1984; 73(2): 169-173.
Prescott LF, Steel RF, Ferroer WR. The effect of particle size on the absorption of
phenacetin in man. Clin Pharmac Ther 1970; (11): 496-504.
Bates TR, Sequeria JA, Tembo AV. Effect of food on nitrofurantoin absorption. Clin
Pharmac Ther 1974; (16): 63-68.
Chiou WL, Smith LD. Solid dispersion approach to the formulation of organic liquid
drugs using polyethylene glycol 6000 as a carrier. J Pharm Sci 1971; (60): 125-127.
Tachibana T, Nakamura A. Beta-carotene-PVP coprecipitates. Kolloid Z Polym 1965;
(203): 130-133.
Newman A. Pharmaceutical amorphous solid dispersions. New Jersey: John Wiley &
Sons, 2015: 470.
Uekema K. Pharmaceutical applications of methylated cyclodextrins. Pharm Int 1985;
(3): 61-65.
Uekema K, Uemura Y, Irie T, Otagiri M. Analysis of interfacial transfer and absorption
behavior of drug following dissolution from -cyclodextrin complexes. Chem Pharm
Bull 1983; (31): 3637-3643.
Uekema K, Otagiri M, Irie T, Seo H, Tsuruoka, M. Improvement of dissolution and
absorption characteristics of phenytoin by a water-soluble -cyclodextrin-epichlorhydrin
polymer. Int J Pharm 1985; (23): 35-42.
Pongwai S, Dangprasirt P. Approaches to improve dissolution of capsule containing a
poorly water-soluble drug: Mefenamic acid. Rangsit Journal of Arts and Sciences 2014;
4 (1): 47-58.
Gantt C, Gochman N, Dyniewicz J. Lancet. Effect of a detergent on gastrointestinal
absorption of a steroid. 1961; 1(7175):486487.

20